Test Code TGRP
Testosterone, Total and Free, Serum

Reporting Name

Testosterone, Total and Free, S

Useful For

This assay is the alternative, second-level test for suspected
increases or decreases in physiologically active testosterone
(preferred: TTBS / Testosterone, Total and Bioavailable, Serum);
indications:

-Assessment of androgen status in cases with suspected or known
sex hormone-binding globulin-binding abnormalities

-Assessment of functional circulating testosterone in early
pubertal boys and older men

-Assessment of functional circulating testosterone in women with
symptoms or signs of hyperandrogenism, but normal total
testosterone levels

-Monitoring of testosterone therapy or antiandrogen therapy in
older men and in females

*Puberty onset (transition from Tanner stage I to Tanner stage
II) occurs for boys at a median age of 11.5 (±2) years and
for girls at a median age of 10.5 (±2) years. There is
evidence that it may occur up to 1 year earlier in obese girls and
in African American girls. For boys, there is no definite proven
relationship between puberty onset and body weight or ethnic
origin. Progression through Tanner stages is variable. Tanner stage
V (young adult) should be reached by age 18.

Day(s) and Time(s) Performed

Monday through Friday; 2 p.m. Saturday and Sunday; Varies

CPT Code Information

84402-Testosterone, free

84403-Total

LOINC Code Information

Test ID

Test Order Name

Order LOINC Value

TGRP

Testosterone, Total and Free,
S

58952-3

Result ID

Test Result Name

Result LOINC Value

3631

Testosterone, Free, S

2991-8

8533

Testosterone, Total, S

2986-8

Clinical Information

Testosterone is the major androgenic hormone. It is responsible
for the development of the male external genitalia and secondary
sexual characteristics. In females, its main role is as an estrogen
precursor. In both genders, it also exerts anabolic effects and
influences behavior.

In men, testosterone is secreted by the testicular Leydig cells
and, to a minor extent, by the adrenal cortex. In premenopausal
women, the ovaries are the main source of testosterone with minor
contributions by the adrenals and peripheral tissues. After
menopause, ovarian testosterone production is significantly
diminished. Testosterone production in testes and ovaries is
regulated via pituitary-gonadal feedback involving luteinizing
hormone (LH) and, to a lesser degree, inhibins and activins.

Most circulating testosterone is bound to sex hormone-binding
globulin (SHBG), which in men also is called testosterone-binding
globulin. A lesser fraction is albumin bound and a small proportion
exists as free hormone. Historically, only the free testosterone
was thought to be the biologically active component. However,
testosterone is weakly bound to serum albumin and dissociates
freely in the capillary bed, thereby becoming readily available for
tissue uptake. All non-SHBG-bound testosterone is therefore
considered bioavailable.

During childhood, excessive production of testosterone induces
premature puberty in boys and masculinization in girls. In adult
women, excess testosterone production results in varying degrees of
virilization, including hirsutism, acne, oligo-amenorrhea, or
infertility. Mild-to-moderate testosterone elevations are usually
asymptomatic in males, but can cause distressing symptoms in
females. The exact causes for mild-to-moderate elevations in
testosterone often remain obscure. Common causes of pronounced
elevations of testosterone include genetic conditions (eg,
congenital adrenal hyperplasia); adrenal, testicular, and ovarian
tumors; and abuse of testosterone or gonadotrophins by
athletes.

Decreased testosterone in females causes subtle symptoms. These
may include some decline in libido and nonspecific mood changes. In
males, it results in partial or complete degrees of hypogonadism.
This is characterized by changes in male secondary sexual
characteristics and reproductive function. The cause is either
primary or secondary/tertiary (pituitary/hypothalamic) testicular
failure. In adult men, there also is a gradual modest, but
progressive, decline in testosterone production starting between
the fourth and sixth decades of life. Since this is associated with
a simultaneous increase of SHBG levels, bioavailable testosterone
may decline more significantly than apparent total testosterone,
causing nonspecific symptoms similar to those observed in
testosterone deficient females. However, severe hypogonadism,
consequent to aging alone, is rare.

Measurement of total testosterone (TTST / Testosterone, Total,
Serum) is often sufficient for diagnosis, particularly if it is
combined with measurements of LH and follicle-stimulating hormone
(FSH) (LH / Luteinizing Hormone [LH], Serum and FSH /
Follicle-Stimulating Hormone [FSH], Serum). However, these tests
may be insufficient for diagnosis of mild abnormalities of
testosterone homeostasis, particularly if abnormalities in SHBG
(SHBG / Sex Hormone Binding Globulin [SHBG], Serum) function or
levels are present. Additional measurements of free testosterone or
bioavailable testosterone are recommended in this situation;
bioavailable (TTBS / Testosterone, Total and Bioavailable, Serum)
is the preferred assay.

Interpretation

Total testosterone and general interpretation of testosterone
abnormalities:

-In prepubertal boys, increased levels of testosterone are seen
in precocious puberty. Further work-up is necessary to determine
the causes of precocious puberty.

-In adult men, testicular or adrenal tumors or androgen abuse
might be suspected if testosterone levels exceed the upper limit of
the normal range by more than 50%.

Monitoring of testosterone replacement therapy:

Aim of treatment is normalization of serum testosterone and LH.
During treatment with depot-testosterone preparations, trough
levels of serum testosterone should still be within the normal
range, while peak levels should not be significantly above the
normal young adult range.

Monitoring of antiandrogen therapy:

Aim is usually to suppress testosterone levels to castrate
levels or below (no more than 25% of the lower reference range
value).

Females:

Decreased testosterone levels may be observed in primary or
secondary ovarian failure, analogous to the situation in men,
alongside the more prominent changes in female hormone levels. Most
women with oophorectomy have a significant decrease in testosterone
levels.

Increased testosterone levels may be seen in:

-Congenital adrenal hyperplasia: nonclassical (mild) variants
may not present in childhood but during or after puberty. In
addition to testosterone, multiple other androgens or androgen
precursors are elevated, such as 17OH-progesterone (OHPG /
17-Hydroxyprogesterone, Serum), often to a greater degree than
testosterone.

-Prepubertal girls: analogous to males, but at lower levels,
increased levels of testosterone are seen in precocious
puberty.

-Ovarian or adrenal neoplasms: high estrogen values also may be
observed, and LH and FSH are low or "normal."
Testosterone-producing ovarian or adrenal neoplasms often produce
total testosterone values >200 ng/dL.

-Polycystic ovarian syndrome: hirsutism, acne, menstrual
disturbances, insulin resistance and, frequently, obesity, form
part of this syndrome. Total testosterone levels may be normal or
mildly elevated and uncommonly >200 ng/dL.

Monitoring of testosterone replacement therapy:

The efficacy of testosterone replacement in females is under
study. If it is used, total testosterone levels should be kept
within the normal female range at all times. Bioavailable or free
testosterone levels also should be monitored to avoid over
treatment.

Monitoring of antiandrogen therapy:

Antiandrogen therapy is most commonly employed in the management
of mild-to-moderate "idiopathic" female hyperandrogenism, as seen
in polycystic ovarian syndrome. Total testosterone levels are a
relatively crude guideline for therapy and can be misleading.
Therefore, bioavailable or free testosterone also should be
monitored to ensure treatment adequacy. However, there are no
universally agreed biochemical end points and the primary treatment
end point is the clinical response.

Free testosterone:

Usually, bioavailable and free testosterone levels parallel the
total testosterone levels. However, a number of conditions and
medications are known to increase or decrease the sex
hormone-binding globulin (SHBG) (SHBG / Sex Hormone Binding
Globulin [SHBG], Serum) concentration, which may cause total
testosterone concentration to change without necessarily
influencing the bioavailable or free testosterone concentration, or
vice versa:

-Treatment with corticosteroids and sex steroids (particularly
oral conjugated estrogen) can result in changes in SHBG levels and
availability of sex-steroid binding sites on SHBG. This may make
diagnosis of subtle testosterone abnormalities difficult.

-Inherited abnormalities in SHBG binding

-Liver disease and severe systemic illness

-In pubertal boys and adult men, mild decreases of total
testosterone without LH abnormalities can be associated with
delayed puberty or mild hypogonadism. In this case, either
bioavailable or free testosterone measurements are better
indicators of mild hypogonadism than determination of total
testosterone levels.

-In polycystic ovarian syndrome and related conditions, there is
often significant insulin resistance, which is associated with low
SHBG levels. Consequently, bioavailable or free testosterone levels
may be more significantly elevated.

Either bioavailable (TTBS / Testosterone, Total and
Bioavailable, Serum) or free (TGRP / Testosterone Total and Free,
Serum) testosterone should be used as supplemental tests to total
testosterone in the above situations. The correlation coefficient
between bioavailable and free testosterone (by equilibrium
dialysis) is 0.9606. However, bioavailable testosterone is usually
the preferred test, as it more closely reflects total bioactive
testosterone, particularly in older men. Older men not only have
elevated SHBG levels, but albumin levels also may vary due to
coexisting illnesses.